Division of Hematology/Oncology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
J Thromb Haemost. 2011 Oct;9(10):2087-96. doi: 10.1111/j.1538-7836.2011.04454.x.
TF is highly expressed in cancerous and atherosclerotic lesions. Monocyte recruitment is a hallmark of disease progression in these pathological states.
To examine the role of integrin signaling in TF-dependent recruitment of monocytes by endothelial cells.
The expression of flTF and asTF in cervical cancer and atherosclerotic lesions was examined. Biologic effects of the exposure of primary microvascular endothelial cells (MVEC) to truncated flTF ectodomain (LZ-TF) and recombinant asTF were assessed.
flTF and asTF exhibited nearly identical expression patterns in cancer lesions and lipid-rich plaques. Tumor lesions, as well as stromal CD68(+) monocytes/macrophages, expressed both TF forms. Primary MVEC rapidly adhered to asTF and LZ-TF, and this was completely blocked by anti-β1 integrin antibody. asTF- and LZ-TF-treatment of MVEC promoted adhesion of peripheral blood mononuclear cells (PBMCs) under orbital shear conditions and under laminar flow; asTF-elicited adhesion was more pronounced than that elicited by LZ-TF. Expression profiling and western blotting revealed a broad activation of cell adhesion molecules (CAMs) in MVEC following asTF treatment including E-selectin, ICAM-1 and VCAM-1. In transwell assays, asTF potentiated PMBC migration through MVEC monolayers by ∼3-fold under MCP-1 gradient.
TF splice variants ligate β1 integrins on MVEC, which induces the expression of CAMs in MVEC and leads to monocyte adhesion and transendothelial migration. asTF appears more potent than flTF in eliciting these effects. Our findings underscore the pathophysiologic significance of non-proteolytic, integrin-mediated signaling by the two naturally occurring TF variants in cancer and atherosclerosis.
TF 在癌性和动脉粥样硬化病变中高度表达。单核细胞募集是这些病理状态下疾病进展的标志。
研究整合素信号在 TF 依赖性内皮细胞招募单核细胞中的作用。
检查宫颈癌和动脉粥样硬化病变中 flTF 和 asTF 的表达。评估暴露于截断 flTF 细胞外结构域（LZ-TF）和重组 asTF 的原代微血管内皮细胞（MVEC）的生物效应。
flTF 和 asTF 在肿瘤病变和富含脂质的斑块中表现出几乎相同的表达模式。肿瘤病变以及基质 CD68(+)单核细胞/巨噬细胞均表达两种 TF 形式。原代 MVEC 迅速与 asTF 和 LZ-TF 黏附，而抗β1 整合素抗体完全阻断了这一过程。asTF 和 LZ-TF 处理 MVEC 可促进外周血单核细胞（PBMC）在轨道剪切条件下和层流条件下的黏附；asTF 诱导的黏附比 LZ-TF 更明显。表达谱和 Western blot 分析显示，asTF 处理后 MVEC 中细胞黏附分子（CAM）广泛激活，包括 E-选择素、ICAM-1 和 VCAM-1。在 Transwell 测定中，asTF 在 MCP-1 梯度下通过 MVEC 单层增强 PMBC 迁移约 3 倍。
TF 剪接变体在 MVEC 上结合β1 整合素，诱导 MVEC 中 CAM 的表达，并导致单核细胞黏附和跨内皮迁移。asTF 在引起这些效应方面似乎比 flTF 更有效。我们的发现强调了两种天然存在的 TF 变体在癌症和动脉粥样硬化中通过非蛋白水解、整合素介导的信号传导的病理生理意义。
